Controversies and evidence gaps in the early management of severe traumatic brain injury: back to the ABCs

Traumatic brain injury (TBI) accounts for around 30% of all trauma-related deaths. Over the past 40 years, TBI has remained a major cause of mortality after trauma. The primary injury caused by the injurious mechanical force leads to irreversible damage to brain tissue. The potentially preventable secondary injury can be accentuated by addressing systemic insults. Early recognition and prompt intervention are integral to achieve better outcomes. Consequently, surgeons still need to be aware of the basic yet integral emergency management strategies for severe TBI (sTBI). In this narrative review, we outlined some of the controversies in the early care of sTBI that have not been settled by the publication of the Brain Trauma Foundation’s 4th edition guidelines in 2017. The topics covered included the following: mode of prehospital transport, maintaining airway patency while securing the cervical spine, achieving adequate ventilation, and optimizing circulatory physiology. We discuss fluid resuscitation and blood product transfusion as components of improving circulatory mechanics and oxygen delivery to injured brain tissue. An outline of evidence-based antiplatelet and anticoagulant reversal strategies is discussed in the review. In addition, the current evidence as well as the evidence gaps for using tranexamic acid in sTBI are briefly reviewed. A brief note on the controversial emergency surgical interventions for sTBI is included. Clinicians should be aware of the latest evidence for sTBI. Periods between different editions of guidelines can have an abundance of new literature that can influence patient care. The recent advances included in this review should be considered both for formulating future guidelines for the management of sTBI and for designing future clinical studies in domains with clinical equipoise.

The Integrative Approach to Assessing and Managing Risk

This chapter articulates the integrative approach to assessing and managing risk in research. This framework is grounded, not in role-related obligations, but in respect for the basic interests of persons. It models uncertainty as a property of a moderately idealized community of diverse experts, and it shows how studies that are designed to reduce conflict or uncertainty within such a community can reconcile the production of socially valuable information with respect for the status of research participants as free and equal. The merits of this approach relative to prominent alternatives, including component analysis, clinical equipoise, the non-exploitation view and the net risk view are elaborated at length. The merits off the integrative approach are demonstrated by showing how this framework allows trial that use response adaptive randomization to be designed in ways that respect a principle of equal concern and a series of related ethical requirements.

Review of Clinical Equipoise: Examples from Oncology Trials

Background: The current standards that govern clinical research have been shaped over the years through many historical, social, and political events. The third principle of the Belmont report, Justice, guides the scientific community toward equal distribution of benefits and risks in research involving human subjects. Clinical equipoise is the status of genuine uncertainty by the investigator about the superiority of one treatment arm over the other. The term clinical equipoise was proposed to provide an ethical ground to conduct randomized controlled clinical trials. Objective: The objective of this review is to provide the reader with an overview about the emergence of the term equipoise and its utilization in randomized controlled trials. Methods: In the current review article, the major oncology clinical trials and relevant patents were reviewed for the application/utilization of clinical equipoise. Results: The concept of clinical equipoise has been challenged and different alternatives were proposed. Yet, these alternatives received numerous critiques and failed to fully replace equipoise. In addition, several patents related to anticancer agents tested in the described studies were examined. No specific reference was made as part of the patent to the status of clinical equipoise. Alternatively, a description of the study arms was provided. Conclusion: There is a need for revisiting the concept of equipoise and its suggested alternatives, for its ethical essence while addressing related challenges.

Methodological Standards for the Design, Implementation, and Analysis of Randomized Trials in Cardiac Surgery: A Scientific Statement From the American Heart Association

Cardiac surgery presents specific methodological challenges in the design, implementation, and analysis of randomized controlled trials. The purposes of this scientific statement are to review key standards in cardiac surgery randomized trial design and implementation, and to provide recommendations for conducting and interpreting cardiac surgery trials. Recommendations include a careful evaluation of the suitability of the research question for a clinical trial, assessment of clinical equipoise, feasibility of enrolling a representative patient cohort, impact of practice variations on the safety and efficacy of the study intervention, likelihood and impact of crossover, and duration of follow-up. Trial interventions and study end points should be predefined, and appropriate strategies must be used to ensure adequate deliverability of the trial interventions. Every effort must be made to ensure a high completeness of follow-up; trial design and analytic techniques must be tailored to the specific research question and trial setting.

Rehabilitation following rotator cuff repair: A survey exploring clinical equipoise among surgical members of the British Elbow and Shoulder Society

Background We investigated clinical equipoise across surgical members of the British Elbow and Shoulder Society (BESS) in relation to rehabilitation following rotator cuff repair. Method An online survey explored clinical equipoise regarding early patient-directed versus standard rehabilitation after rotator cuff repair to inform the design of a national randomised controlled trial (RCT). It described different clinical scenarios relating to patient age, tear size, location and whether other patient-related and intra-operative factors would influence equipoise. Results 76 surgeons completed the survey. 81% agreed/ strongly agreed that early mobilisation might benefit recovery; 57% were neutral/ disagreed that this approach risks re-tear. 87% agreed/ strongly agreed that there is clinical uncertainty about the effectiveness of different approaches to rehabilitation. As age of the patient and tear size increased, the proportion of respondents who would agree to recruit and accept the outcome of randomisation reduced, and this was compounded if subscapularis was torn. Other factors that influenced equipoise were diabetes and non-secure repair. Conclusion Surgical members of BESS recognise uncertainty about the effectiveness of different approaches to rehabilitation following rotator cuff repair. We identified a range of factors that influence clinical equipoise that will be considered in the design of a new RCT.

Contemporary Management of Cardiogenic Shock: A RAND Appropriateness Panel Approach

Background: Current practice in cardiogenic shock is guided by expert opinion in guidelines and scientific statements from professional societies with limited high quality randomized trial data to inform optimal patient management. An international panel conducted a modified Delphi process with the intent of identifying aspects of cardiogenic shock care where there was uncertainty regarding optimal patient management. Methods: An 18-person multidisciplinary panel comprising international experts was convened. A modified RAND/University of California Los Angeles appropriateness methodology was used. A survey comprising 70 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9: 1 to 3 inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. A summary of the results was discussed as a group, and the survey was iterated and completed again before final analysis. Results: There was broad alignment with current international guidelines and consensus statements. Overall, 44 statements were rated as appropriate, 19 as uncertain, and 7 as inappropriate. There was no disagreement with a disagreement index <1 for all statements. Routine fluid administration was deemed to be inappropriate. Areas of uncertainty focused panel on pre-PCI interventions, the use of right heart catheterization to guide management, routine use of left ventricular unloading strategies, and markers of futility when considering escalation to mechanical circulatory support. Conclusions: While there was broad alignment with current guidance, an expert panel found several aspects of care where there was clinical equipoise, further highlighting the need for randomized controlled trials to better guide patient management and decision making in cardiogenic shock.

Nebulised liposomal-amphotericin-B as maintenance therapy in ABPA: a randomised, multicentre, trial

BackgroundIn allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission.MethodsWe performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after a 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal-amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time-to-first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters.ResultsAmong 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) of 65 patients in nebulised liposomal-amphotericin-B group and 38 (51.3%) of 74 in placebo group (absolute difference −0.6%, 95% CI −16.8% to +15.6%, odds ratio 0.98, 95% CI 0.50 to 1.90; p=0.95). The median time-to-first severe clinical exacerbation was longer in liposomal-amphotericin-B group, 337 days (IQR, 168 to 476) versus 177 (64 to 288). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in nebulised liposomal-amphotericin-B group.ConclusionsIn ABPA, maintenance therapy using nebulised liposomal-amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Ethical Considerations in Conducting Paediatric Research

Health research is a moral duty because it is the foundation for evidence-based care by all health care practitioners. Hence, paediatric research is essential for improving health outcomes of children. Waiting for adult studies before conducting paediatric studies may prolong the denial of effective treatment for children. The CIOMS and other guidelines clearly allow research procedures that involve a low degree of risk. However, the critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. Even in a resource poor setting of a developing country like Bangladesh, the things that should be taken under considerations are the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; ethical considerations underlying study design, including clinical equipoise, placebo controls, and non-inferiority designs; the use of data; compensation; and parental permission and child assent where applicable to participate in research. Such ethical dilemmas are more evident in paediatric research especially when a collaborative research is done by a developed country in a developing country setting. It is the role of the health policy makers, and community of paediatric physicians, nurses, and caregivers to advocate not only for more research for children but also to ensure that the research conducted is of the highest quality from ethical viewpoint. CBMJ 2020 July: Vol. 09 No. 02 P: 54-58

113 Simplifying consent - Use of the novel integrated consent model in paediatric clinical research

Primary Subject area Hospital Paediatrics Background Obtaining informed consent from patients to participate in clinical research has traditionally been a cumbersome process, often requiring lengthy documentation and the involvement of trained research staff. Moreover, this process can be a burden to the patient/family. As a result, progress in paediatric research and enabling continual improvement in care has been slow. In the last decade, research ethicists have proposed a new “integrated consent model” (ICM) for obtaining informed consent for pragmatic clinical trials that compare standard-of-care interventions, where there is clinical equipoise. In most cases of ICM, only a brief discussion with verbal consent is required, along with a handout on study purpose, risks, benefits, and procedures. This allows for a more condensed consent process, which maximizes clarity and minimizes information overload. ICM also allows the patient/family to maintain prospective autonomy and decision-making, as compared with deferred or waived consent. The ICM model allows staff in the circle of care to obtain consent, which minimizes the stress of meeting an additional person. To our knowledge, ICM has not yet been used in the paediatric population. Objectives The objective of this abstract is to report on the utility of ICM in a non-randomized clinical trial carried out in the inpatient setting of a tertiary children’s hospital. Design/Methods We compared two widely accepted standards of care for maintaining peripheral intravenous catheter patency in a cohort of children, namely continuous infusion (“to keep the vein open” or TKVO) versus saline lock (SL). The ICM process was reviewed and approved by REB. Nurses in the circle of care received a study package that included an REB approved “consent script” to be read to the patient/family, a single page information sheet, and instructions on documenting the obtained verbal consent in the patient’s chart (Graphic 1). Results With ICM, 79% of participants were recruited into the trial by a nurse. Patient recruitment was completed 4 months ahead of the predicted schedule (Figure 1). Nursing, research, and medical staff were satisfied with ICM and found it easy to administer. ICM occurred smoothly and quickly for patients/families, with no interference with their medical care and practically no disruption to their daily schedule. Conclusion ICM is a practical alternative to laborious traditional consent models, is associated with higher patient recruitment rates, and is less burdensome for the patient/family. Paediatricians should be aware of the utility of this novel consent model.